SUBSTITUTED 2,4(~H,~H)-QVI;VAZOLISEDIOSES
Soveinher 196,;
with gaseous HBr and allowed to stand at ambient temperature for 18 hr. The mixtiire was evaporated zn cacuo. The residiial oil was dissolved in a minimum of methanol, basified with 5y0 aqueous Na2C03,and extracted with CHCI,. The dried (hlgSO4) CHCl, extract was evaporated in vacuo leaving an oil (1.1 g.)
807
which by infrared analysis was shown to be a nnstiire composed mainly of 2-rnethy1-2-(p-hydroxyphenethyl)nicotinir arid hydrazide and 2-meth~1-2-(p-acetoxypheiiethyl)1iicotiriic acid hydrazide; vmsx (film) 3390-3180 broad (OH, S H ) , 1T26 ( w t e r carbonyl), and 1695 (hydrazide carbonyl) cm.-l.
New Sedative and Hypotensive 3-Substituted 2,4(1H,3H)-Quinazolinediones SHIS HATAO,HERBERT J. HAVERA, WALLACE G. STRPCKER, T. ,J. LEIPZIG, RICHARD -4.KULP.A N D HAROLD E. HARTZLER Chrniicnl Thrrapeictz'cs Research Laboratory, X i l e s Laborntorips, Inc., Elkhnrl, Inrliann
Received April 12,1965 A series of 3-sitbstitiited 2,4( lH,3H)-qiiinazolinediones, mostly 3-(4-aryl-l-piperazinylalkyl)-2,4( lH,3H)qiiinazolinediones, was prepared from the corresponding o-amino-N-sitbstitiited benzamides by treatment with phosgene in boiling chlorobenzene. 1-hIethyl-3-substituted 2,4( 1H,3H)-qiiinazolinediones were prepared by the reaction of o-methylamino-N-substituted benzamides with ethyl chloroformate, followed by heating at 200" to cyclize. These compoiinds showed varying degrees of sedative and hypotensive activity in experimental animals.
It has been reported that 2,4(1H,3H)-quinazolinediI was also prepared by treating I1 with ethyl chloroformate, followed by heating at 200" to cyclize. oiie1J and 1,.3-diniethyl-2,4(1H,3H)-quina~olinedione~~~ possess anticonvulsant3 activity against electroshock The formation of the quinazoliriedione (I) (Scheme I) and pentylenetetrazol seizures in mice. 3-Alkyl-, 3by treatment of o-amino-S- [3-(4-phenyl-l-piperazinyl)aralkyl-, and 3-aryl-2,4(1H,3H)-quinazolinediones4 propyllbenzaniide (11) with phosgene at the boiling have been described but no pharniacological screening point of chlorobenzene was presumed to proceed results were given. Our finding thaf some amides through the intermediate isocyanate (IV) formed by derived from 4-aryl-l-~~iperaziriylalliylamines,~ 4-aryl-ldehydrochlorination of the carbamoyl chloride (111). piperazinylalkanoic acids,j and S-(4-aryl-l-piperazinylUnder the same conditions, o-methylamino-N- [3-(4alkyl) derivatives of cyclic imides6 have shown sedative phenyl-1-piperazinyl)propyl]benzamide (V) gave the and hypotensive activities led 11s to prepare 3-substicarbamoyl chloride (VI) in high yield (Scheme 11). t uted [mostly 3-(4-aryl-l-piperazinylalkyl)-2,4 (lH,SCHEME I1 8H)-] quinazolinediones (I). The reaction of primary amines with isatoic anhyC0NHR.H C1 dride gives mainly o-aniin~benzaniides~ with minor N (CH,)COCI quantities of l-nlky1-3-(o-carboxyphenyl)ureas.4b The v VI latter compouiids are readily cyclized with dilute mineral acid to give I. In our hands, o-amino-S-alkyl- (or CICOOC.H aralkyl-) benzamides (11) cyclized readily with phosf) gene i n boiling chlorobenzene to give I in high yield.
@E: a0 1
C0NHR.H C1 N(CH JCOOC,H
SCHEME I CONHR
coci
C1 C,H
~
[@
I1
CONHR NH COCl
R = -(CH~),N"N
I11 0
DEE0 -] &go IV
I
CHJ VI1
H I
(1) J. H. Rurckhalter and H. C. Scarborough, J . Am. Pharm. Assor.. Sci. Ed., 44, 545 (1955). (2) B. Das a n d R. hlukherjee, J . Indian Chem. Soc., 40, 35 (1963): Chem. Abstr., 59, 6404 (1963). ( 3 ) D. G. Wenzel, J . Am. Pharm. Assoc., Sei. Ed., 44, 550 (1956). (4) (a) C. P a d , Ber., 27, 974 (1894); (b) R . P. Staiger a n d E. C. Wagner, J . O r g . Chem., 18, 1427 (1935); ( e ) C. H. Wang, T . C. Feng, a n d B. E. Christensen. J . Am. Chem. Sor., 72, 4 8 8 i (1950); (d) n. T a u h a n d J. 13, Hino, J . Orb-. Chem., 96, 5238 (1961). ( 5 ) S. Hayao a n d R. S . Rchut, ihid.. 26, 3414 (1961). (6) S. Hayao and \V.G . Strycker, unpublislied data. ( i ) R . H. Clark and E. C. Wagner, J . OTQ.Chem., 9, 55 (1944).
c,H,
W The dehydrochlorination of VI to give isocyanate is riot possible in the latter case. 1-Methyl-3- [3-(4-phenyl-lpiperaziny1)propyl 3 -2,4( lH,3H)-quinazolinedione(VII) was obtained by treating V with ethyl chloroformate, followed by heating at 200". See Table I for conipounds I and VII. 2-Thio-2,4(1H,3H)-quinazolinediones(VIII) were prepared by adding I1 to a solution of thiophosgene in chlorobenzene, followed by heating under reflux to cyclize (see Table 11). 0 CSCL CIC H,
11
.
dz S
H VI11
808
R
I1 11 H
H
H
H H H H
H H H H H
H CHjCOSH
H H
H
H
H
H
('I
H
H
H
H
H
('I
H H CHI
H
("3
('1 PH3 A1aleat.e. Basic nitrogel\. Titrated tiy HC101. L 1 7 ~ a l . C d c d . : HCI, 1N.O. F(iuiitI: HC'I, I6.0. d S.40. Found: HC1, 8.48. e . I n d Calcd.: HCI. 8.38. Found: HCI, 8.38. .' IIethosulfate. -Lnnl. For~nd: HCI, 16.1. .Inal. Calrd.: HC1, 8.13. Foulld: HC'I. 8.12. ' Anal. C a l d . : HCI, 15.7. j Anal. Calcd.: HC1, 8 . 2 5 . Found: HCl, 8.40. .!nul. Calcd.: HC1, 16.3. Fourid: HC1, 16.1. / 8.12. Found: HCl, 8.18. -4nol. Calcd.: HC1,8.18. Found: HCI,X.OS. a
Pharmacology.---These cwmpouiids .show varyill# degrees of sedative arid hypotensive. aotivity. One of the best compounds as a poteiitial p.*ychosedat ive ~va. 9b (Table I). Its actirity in experimental animals \m* c.onil)uable to that of chlorproriia,zirie (CPZ). Thi. i,. > h o \ v i i hy t h e followiiig t c s t s : ( I ) double blitrcl hi>-
A n d . Calrd.: Calcd.: HCII. Found: HCI, .1nal. Calcd.:
HC'I, 16.2. 15.8,
HCI,
Iia,vioral observations in dogs m d cats;, ( 2 ) loconlotor activity iisiiig n mtnrod,8 (?) ac'tivity (.agesg wit,h niiw. ( 8 ) S . R'. I ) ~ r n i i u ~ ran,! i
1'. ,*, A i j h a , J . . 4 m . I'hmrrii,
46;;,"P"(,1~~,i~vintpr ,,,,, I,, , : l n ~ ~ ,,, l ~ ~ ~ ,
,,hnr.lllarol, ~
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ISI~I),
. ~ M w . , .Sc,t.
/;it.,
; ~ , /~ , ~ , , ,~ 103, ~ ~ , ,~
~
~
809
November 1963
No.
X
28
H
R
Y
H
H
0
30 H 31 H
H H
0 2 0 2
32
H
0 2
29
H
1
%---
N
---Found. C
%--H
17.6
>260
0 0
H
---Calcd., C H
M.p., o c .
n
265-267 der.
56.6 3.63
238-239 245-247 2 15-2 16 202-203
6 6 . 5 4.35 58.0 4.15
275-278
70.9 4.92
15.3
N
17.6 56.9 4.14
15.3
6 6 . 3 4 . 4 0 16.7 16.6 4.83c 5 7 . 4 4.33 4.72 10.5 10.8 6 6 . 3 5 . 5 3 8 . 6 0 66.1 5 . 4 5 8.83 13.8
70.2 5.01
13.7
H
I
33
H
C.Jo
0 2
H
I
210 dec.
C2QH22N402.2HCl.CH40dle
12.3
12.2
CH3
c I
2 17-218
57.7 5.99 12.8
57.4
6.08
12.8
58.0 7.62
13.7
H
H
0
3
35 H
H
0
3
227-228
5 7 . 7 7.06
3
168-169 242-243 181-183 dec.
62.5 6.25 14.6 12.9 53.2 5 . 6 7 9 . 9 3
61.9
166-167 >260 233-234
70.5 7.15 5 6 . 5 5.35
14.3 12.1 8.50
70.2 7.21 14.5 12.1 56.7 5.44 8 . 5 0
172-176 210-202
7 2 . 8 6 . 9 0 11.6 65.2 6 . 0 5 8 . 7 7
72.6 6.40 11.9 65.0 5 . 6 6 8 . 8 8
185-188 der.
65.7 6.09
65.6 6 . 4 5
34
36
H
H
0
37
H
H
0
3
38
H
H
0
3
39
Cl
H
0
3
--.N
40
H
H
0
3
-N>
41
H
CH3
0
3
42
Cl
H
0
3
n NCHZCH, CeH, u C,H,
C,H,
-N>
43
H
H
0
3
44
H
H
s
3
-N
45
C1 H
s
3
--NA~-c,~,
46
H
S 6
H
n
NC,H,CI-m
U
W
--N
A
N-CSH,
v
13.5
8.52
6.57
14.7 12.8 53.8 5.90 9.86
10.6
198-199.5
8.18
8.72 10.7
221.5-222 5 dec. 260-250 5 dec. 212-2 13
60.8 5.45
61.1 5.94
56.7 5.14 10.5
5 6 . 9 6.02
213-215 >280 262-264
60.8 5.55 13.5 5 5 . 9 5 . 3 3 3.13' 57.4 6.29 11.6
6 0 . 8 5.95 1 3 . 1 55.7 5.74 3.23 57.7 6 . 5 8 1 1 . 7
10.1
8.08 10.3 10.6
a Anal. Calcd.: HC1, 13.2. Found: HCl, 13.2. Anal. Calcd.: HC1, 12.7. Found: HCl, 12.3. Basic nitrogen. Titration with HC104. d Methanolate. e Anal. Calcd.: HC1, 16.1. Found: HC1, 16.0. f Anal. Calcd.: HCl, 11.3. Found: HC1, 11.4. Maleate. Anal. Calcd.: HC1, 15.7. Found: HC1, 15.7. Bnal. Calcd.: HC1,8.79. Found: HC1, 8.73. Anal. Calcd.: HCl, 8.10. Found: HC1, 8.05. Q
J
(I)hexobarbital sleeping time prolongation in mice,'O
(5) lowering the threshold current for psychomotor seizure in mice," and (6) lowering the acute d-amphetamine toxicity in aggregated mice.I2 Equal prolongation of the hexoba,rbital sleeping t,imes (mg. for mg.) (10) c. b. m-inter, J. Pharmacal. Ezptl. Therap., 94, 7 (1948). (11) G . Chen, c. R. Enson, a n d R. Bohner, proc.sot. E z p t l . ~ i ~.wed. l . 86,507 (1954). (12) (a) J. H. B u r n a n d R. Hobbs, Arch. intern. pharmacodyn., 113, 290 (1958); (b) G . S.Stone. n. M. Bernstein, W.E. Hambourger, a n d V. A. Drill, ibid.,127, 8.5 (1960).
were obtained with 9b and CPZ. At a dose 5-10 times that' of CPZ, 9b depressed spontaneous motor activity in mice and rat's to t'he same extent' as did CPZ. In the rot'arod test, the EDSOof 9b mas 2.9 mg./kg. and that of CPZ was 1.6 mg./kg. I n a blind crossover behavioral study in dogs and cats, 9b a t 5 mg./kg. ( p . 0 . )produced sedation equal to that produced by CPZ in dogs and produced great'er (1.9 times) sedation in cat's than did CPZ at' the same dose. The toxicity of 9b was very low: LD,, >7650 (rat, P . o . ) , 3290 (rat', i.p.), and 2160
slow stream of phosgene during $40 min. to give a tan solid. The reaction mixture was kept at room temperature overnight and the solid was Collected on a filter, m.p. 170-210° with soft,eiiiiig a t 120°, yield 99.1g. The free base was obtained by treating the criide hydrochloride with aqiieoiis XH3. The base was recrystallized twice from aqiieoLis methanol-DRIF to give a deep yellow solid of m.p. 208-210D; yield 50.0 g. ; u:~~' 1725 and 1670 (imide carbonyls), 1540 and 1340 em.-' (NOS). From the rerrpstallization mother liqiior, 29.5 g. of crude starting material was obtained by adding excess water, m.p. 129-139'. 5.-1-( 2 -Carhoxy-4-nitrophenyl) -3- [ 3 - (4-phenyl- 1-piperazinyl)propyl] urea ( 13 g. ) was recrystallized twice from aqueous 1)llF-methanol to give a yellow solid of m.p. 208-210", yield 8.0 g. The melting point of a mixtiire with the prodiict from method A was not depressed. The infrared spectra were identical. ilnal. Calcd. for C ~ I H ~ ~ XN, ~O 17.14. $: Found: S, 17.07. 6-Amino-3- [ 34 4-phenyl-1 -piperazinyl)propyl]-2,4( 1H,3H)quinazo1inedione.-The above nitro compound (50.0 g., 0.123 mole) was hydrogenated using 10 g. of palladium on charcoal (5c$ P d by weight) i n 400 ml. of glacial acetic acid under 3.5 kg. (50 lb.) initial hydrogen presslire a t room temperatiire. The calculated amoiint of hydrogen was taken np in 30 min. The catalyst was removed, and the solvent was evaporated in uacuo t o leave a brown viscons syriip which was treated with aqueous NH3 to give a solid of m.p. 229-235', yield 46.9 g. This was recrystallized from aqiieoiis methanol-DlIF (carbon) to give a brown powder of m.p. 2334-288', yield 37.9 g. The amino derivative is rinstahle i n air. 6-Acetamido-3- [ 34 4-phenyl-l-piperazinyl)propyl]-2,4( lH,3H)quinazolinedione Maleate (17).-The above amino derivative (:30.2 g.) was hydrogenated again in a mixture of glacial acetic acid (200 ml.) and acetic anhydride ( 5 0 ml.) with 5 g. of palladium o n carboil ( S 5 Pd by weight) to reduce any oxidized material. The prodiict was obtained as described above, yield 27.2 g., m.p. 258-262" (softening at 252"). It was recrystallized from aqiieoiis methanol-IllIF to give a tan powder of m.p. 2 5 i 261" dec., yield 18.1 g. It was siispeiided in methanol, maleic acid (5.8 g., 0.05 mole) was added to give a slurry which was dissolved i n aqueous methanol-DlIF, aiid the solution was treated with charcoal and concentrated. Addition of ethyl acetate gave a piire maleate of m.p. 245-246' dec.; yield 19.7 g.; ULZ 1710 and 1650 (imide carbonyls), 1650 cm.-I (AcNH). .lnaZ. Calrd. for C ~ ~ H Z , N ~ O : I . C ~ C,H60.3; ~ O ~ :H, 5.77; K', 13.0. Foiind: C, 60.0: H , .5.50; N, 13.0. o-Methylamino-N- [ 34 4-phenyl-l-piperazinyl)propyl] benzamide.-A mixture of 1-niet,hylisatoic anhydride (54.0 g., 0.308 mole) and 1-(S-aniinnpropyl)-4-phenylpiperazine(66.9 g., 0.305 mole) was heated on a steam bath for 1 hr. after the initial reaction had sitbsided. The resiilting solid was recryst,allized from ayiieolis acetone to give a colorless crystalline solid of n1.p. 127129"; yield 91.2 g . ( 8 6 5 ) : Y:::,"~ 33345 (broad XH), 1640 (amide C=O), 1520 cm.-' (amide 11). .trial. Calcd. for C?IH&'&: S , 15.9. Foiind: K,16.1. o-( N-Chlorocarbonylmethylamino)-N-[ 34 4-phenyl-1 -piperazinyl)propyl]benzamide Hydrochloride.-Dry phosgene was bubbled into a boiling solution of o-methylamino-K- [3-(4-phenyl1-piperaziny1)propyllbenzamide (49.1 g., 0.14 mole) in 250 nil. of chlorobenzene during 45 niin. with vigorous stirring to give a slightly tan solid. After cooling to room temperature, ethyl acetate was added, and the solid was collected on a filter, washed with et,hyl acetate and ether, and dried in air; m.p. 227-228" dec.; yield 61.4 g.; u 2 3 1780 (COCl), 1750, 1645 cm.-l (amide C=O), no amide I1 band. :lnal. Calcd. for C~~Hy~C1N40,.HC1: ?i, 12.4. Foiind: N, 12.5. The above hydrochloride (50.6 g.) was recrystallized twice from aqiieoiis 2-propanol containing HC1 t o give the trihydroc*hlorideof the starting material, m.p. 218-219" dec., yield 39.5 g . Anal. Calcd. for C ~ I H ~ I C l ~ NHC1, ~ O :23.7. Found: HCI, 23.7. 1-Methyl-3- [3-(4-phenyl-l-piperazinyl)propyl] -2,4( 1H,3H)quinazolinedione (25).-To a boiling solution of o-methylaminoK-[3-( 4-phenyl-l-piperazinyl)propyl]benzaniide (54.6 g., 0.155 mole) in 250 ml. of dry tetrahydrofuran was added a solution of ethyl chloroformate (17.4 g., 0.16 mole) in 50 ml. of tetrahydrofuran dropwise during 10 min. to give a milky solution which was heated under reflux for 1 hr. and then kept at room temperatiire overnight. The solvent was removed in uacuo and the residue (sticky semisolid) was heated a t 200-235' in a wax bath for .5 hr. to give a brown solid mass. This was dissolved in hot niethaiiul and treated with dry HCl to give a light tail solid of 1ii.p. 248-252' dec., yield 58.3 g. Recrystallization from aqueous
met,hanol containing HCl and ethyl acetate gave 48.1 g. of a colorless solid of m.p. 248-250" dec. This was dissolved iri water and made basic with aqiieoris NHI to give a colorless sirup which soon solidified on scratchiiig. Recrystallization from aqueous acetone gave a colorless solid of m.p. 97-98'; yield 39.0 g.; u ::;' 1660 and 1705 (imide carbonyls), no amide I1 and NH. The free base was dissolved in 200 ml. of methanol and added to 200 ml. of methanol saturated with dry HC1 t o give a colorless solid. This was collected on a filter, washed with ethyl acetate and ether, and dried in air; m.p. 247-249' (dark melt); yield 44.1 g.; :::u 1660 and 1705 (imide carbonyls), no amide 11. 6-Chloro-3- [3-(4-phenyl-l-piperazinyl)propyl]-2-thio-2,4( 1H,3H)-quinazolinedione (45).-To a suspension of 2-aniino-5chloro-N-[3-(4-phenyl-l-piperazinyl)propyl] benzaniide ( 2 5 . 0 g., 0.067 mole) in 250 ml. of chlorobenzene a t room temperature was added a solution of thiophosgene (8.0 g., 0.076 mole) in 50 ml. of chlorobenzene dropwise during 10 min. with stirring to give a milky siispension. Heating a t reflux for 1 hr. gave a mixture of a light solid and a very dark blue solid. The solid was collected on a filter and washed with ethyl acetate and ether, and the still solvated solid was treated with aqueous ammonia to give a light tan oil which partly solidified. This was extracted with chloroform and an insolitble solid was collected on a filter. The chloroform layer was separated and dried. The solvent was removed in uacuo to give a mixtiire of tan and greenish bliie solids. The mist'iire was tritrirated with ether and the insoluble solid was collected o n a filter; yield 7.7 g., m.p. 184-200". The chloroform-insoluble solid melted at 188-205', yield 16.7 g. Both solids were combined and recrystallized from aqueous methanolDAIF (carbon) to give a light greenish blue solid of m.p. 201210", yield 19.9 g. Two more recrystallizations gave a light greenish yellow solid of m.p. 213-215', yield 16.0 g. The base in methanol was treated with dry- HC1 to give a piirple solid. Enough aqiieoiis 1)MF was added to the boiling siispeiisiori to yield a clear soliition which was filtered hot. The filtrate deposited a colorless hydrochloride on cooling; vield 14.2 g.; m.p. >280°; :::u 3180 ( S H ) , 1680 (imide C=O), l j 3 5 (t,hioimide 11),1330 (t.hioimide 111),1170 and 1150 cm.-' (thioimide C=S).zO N-Methyl-N-phenethy1enediamine.-X-llethylaniline (321 g., 3 moles) was added to a mixture of 3iyc formalin (243 nil,, 3 moles) and sodium bisulfite (312 g., 3 moles) in 1000 nil. of water. The mixture was stirred a t 70-80' for 2 hr. and 195 g. ( 3 moles) of KCN was added. After reflrixing for :3 hr., the reaction mixtlire was extracted with ether. The ether extract was dried, and the solvent mas removed in z'acuo t o leave a liqiiid of b.p. 97-YX" (0.5 mm.), yield 332.8 g. (75.5:;). This was N-methyl-Ncyanomethylaniline. The nitrile was hydrogeiiated i l l methanolic ammonia iising a Rariey nivkel catalyst at 100' at 70.8 kg. (1000 lb.) pressure. The crude amine was distilled at 148' (1:J mm.), yield 226.5 g. (67y0),lit.*I b.p. 145' (13 mm.).
2,3,4,5-Tetrahydro-l-methyl-l,4-benzodiazepine.-S-lIethylN-phenylethenediamine (166.2 g., 1.1 moles) was added slowly to 250 ml. of 90% formic acid a t ca. 10". After the addition of 90 nil. (1.11 moles) of 375% formalin, the mixture was heated a t 90" for ca. 60 hr. wit,h st,irring. The cooled solution was added to ice and basified with NaOH solution, and the resulting amine was extracted with chloroform. The extract was dried and evaporated in uacuo to give the 5-formyl derivative, which was hydrolyzed by heating in 18% HC1 overnight. The acidic solution was concentrated in uacuo, and the residue was basified with XaOH solution. The resulting amine was ext.racted with ether and dried. After removing the solvent, the amine distilled a t 87-93' (0.43 mm.), yield 45 g. ( 2 5 ' 3 ) . Anal. Cal(2d. for CloH,4Nz: S(basic), 8.64. Foiuid: N(basic), 8.63 (titration with HClOd).
Acknowledgment.-The authors wish to express their gratitude to Dr. Otis E. E'ancher, director of this laboratory, for his guidance and encouragement throughout this work, to Drs. Hiroshi Fujimori arid E. Soaje Echague and A h . D. P. Cobb for the pharmacological screening data, and to X r . F. R. Bunn and Mrs. Elva Kurchacol-a for analytical and spectral data. (20) (a) K. Nakanishi, "Infrared Ahsorption Spectroscopy-Practical," Holden-Day, Inc., Pan Francisco, Calif.. 1962, p. 54; (b) 11. Yamaguchl and 8. X a t s u k a u - a . "Sekigaisen-Ryushu Spectra," Vol. 16, Nankodo Company Ltd.. Tokyo, 1964, pp. 135-150 (in .Japanese). (21) H. .b-clier, T . R . Lewis, 11. J. Lrnser, .J. 0. H o i ~ y e .and 13. Lape. J . A m . Chem. Sac., 79, s i 8 3 ( l Y 5 i ) .
